The epicardium : contribution from the haematopoietic lineage and its potential as a stem cell niche The epicardium : contribution from the haematopoietic lineage and its potential as a stem cell niche

The adult mammalian heart is no longer considered a post mitotic organ with evidence for homeostatic cell turnover and presence of populations of resident cardiac stem/progenitor cells. The epicardium is a single cell layer surrounding the myocardium and derives from the proepicardial organ during development. It has an important role in formation of the coronary vessels and the embryonic myocardium but, until recently, was considered to be quiescent in the adult heart. Recent studies have shown that reactivation of the adult epicardium post myocardial infarction (MI) injury induces a population of epicardium-derived progenitor cells (EPDCs) to proliferate, migrate and differentiate in the scar region. It remains unclear whether these EPDCs reside in an epicardial niche within the adult heart as classically defined in other lineages, such as the hair follicle bulge and intestinal crypt. Using confocal microscopy, we have identified cell clusters located in the intact epicardium, which express key extracellular matrix (ECM) and stem/progenitor cell markers and respond dynamically to injury, with cluster reformation occurring by day 21 post MI. We suggest that these clusters are candidates for a putative epicardial niche in the adult heart. Lineage tracing analyses to determine the origin of cells residing within the clusters have excluded Wt1+ or Gata5+ proepicardial lineages, but suggest a haematopoietic source. Using Vav1Cre; ROSA-tdTomato to label haematopoietic cells, we have shown that cells from the haematopoietic lineage contribute to the adult epicardium. We have tracked this contribution through development and into adulthood and show an increase in incidence of cells of the haematopoietic lineage in the epicardium with age. Results from bone marrow (BM) transplantation experiments, using whole BM we have shown contribution to the adult epicardium from BM cells. Labelling donor cells using Vav1Cre; ROSA-tdTomato shows that these cells are of haematopoietic lineage. These data suggest haematopoietic cells represent a novel source of cells that contribute to the epicardium during development and that are likely involved in replenishing epicardial cell turnover during cardiovascular homeostasis and may participate in cardiac repair.